The present invention, in some embodiments thereof, relates to therapy, and more particularly, but not exclusively, to novel methods of treating proliferative disorders.
Chemiluminescence is light resulting from a chemical reaction which produces an intermediate in an excited electronic state. The excited intermediate decays into an electronic ground state through fluorescence or phosphorescence, depending on the spin state of the excited intermediate, thereby producing light.
Chemiluminescence may be produced by a variety of structurally unrelated compounds.
FIG. 1 presents the chemical structures of representative members of some families of chemiluminescent compounds.
Some compounds emit chemiluminescence upon oxidation, for example, via reaction with reactive oxygen species (ROS).
One family of such compounds comprises compounds having a 1,2-dihydropyridazine-3,6-dione moiety, such as derivatives of 2,3-dihydrophthalazine-1,4-dione (e.g., luminol, isoluminol) and 2,3-dihydropyridopyridazine-1,4-dione (e.g., L-012) (see, FIG. 1).
U.S. Pat. No. 5,420,275 and European Patent Application EP 01491477 describe chemiluminescent pyridopyridazine compounds such as L-012, and uses thereof for assays.
Coelenterazines such as CLA and MCLA (see, FIG. 1) also produce chemiluminescence upon reacting with ROS.
Lucigenin (see, FIG. 1) represents another family of compounds which produce chemiluminescence upon reacting with ROS.
In a somewhat different mechanism, oxalate derivatives produce chemiluminescence in combination with a fluorescent molecule. Upon reacting with ROS, oxalates are oxidized to produce a 1,2-dioxetanedione intermediate. This intermediate decomposes while transferring energy to a fluorescent compound, which then emits light. The emission wavelength can be controlled by selecting different fluorescent compounds.
Some compounds produce chemiluminescence when acted upon by a suitable enzyme.
For example, chemiluminescence may be produced by firefly luciferin in the presence of ATP, luciferase and magnesium ion.
In addition, stable dioxetane compounds may decompose when acted upon by a specific enzyme, thereby producing chemiluminescence.
U.S. Pat. No. 5,094,939 describes stabilized dioxetane derivatives comprising a phosphate moiety, which decompose following cleavage of the phosphate moiety by a phosphatase, generating products which emit chemiluminescence. AMPPD (disodium 3-(4-methoxyspiro{1,2-dioxetane-3,2′-(5′-chloro)tricyclo[3.3.1.1]decan}-4-yl)phenyl phosphate; also referred to in the art as “CSPD”) is described therein as an example of a stabilized dioxetane derivative (see, FIG. 1).
Similarly, dioxetane derivatives have been prepared, which produce chemiluminescence when hydrolysed by a peptidase [Richard et al., Organic Letters 2007, 9:4853:4855].
Chemiluminescence in the presence of a photosensitizer has been used to activate photosensitizers in order to destroy cells.
U.S. Pat. No. 7,772,179 describes methods utilizing a chemiluminescent agent and a conjugate comprising a photosensitizer linked to a transport ligand, for selectively destroying target cells and for treating a disorder associated with undesired activity of a cell population. The methods are exemplified therein by the use of a transferrin-hematoporphyrin conjugate with luminol as a chemiluminescent agent.
Carpenter et al. [Proc Natl Acad Sci USA (1994) 91:12273-12277] describes the use of a luciferin/luciferase reaction for activating a hypericin photosensitizer, and the subsequent destruction of equine dermal cells.
Theodossiou et al. [Cancer Res (2003) 63:1818-1821] describes the use of a luciferin/luciferase reaction for activating a rose bengal photosensitizer in luciferase transfected murine fibroblasts.
Phillip et al. [Oncology (1989) 46:266-272] describes an attempt to use the photosensitizer Photofrin II in combination with a chemiluminescent system comprising substituted oxamide, rubrene, a surfactant, and hydrogen peroxide, in order to treat tumors in mice. The results presented therein show that the anti-tumor effect is not dependent on light emission.
Refined monosodium luminol is sold under the trade name Galavit™, and exhibits antioxidant properties which may be useful for treating disorders associated with oxidative stress [Jiang et al., J Virol 2006, 80:4557-4569]. There have been controversial claims that Galavit™ can be used to treat cancer, but these claims have not been substantiated, and have even resulted in criminal convictions for selling a fraudulent cancer cure [Tuffs, BMJ 2008, 337:a875].
Additional background art includes International Patent Application PCT/US2009/063186 (published as WO 2010/062787), International Patent Application PCT/US2007/064919 (published as WO 2007/112347), International Patent Application PCT/JP2008/065286 (published as WO 2009/028543), International Patent Application PCT/US2006/061890 (published as WO 2007/081630), International Patent Application PCT/US2001/13730 (published as WO 2001/082780), U.S. Patent Application Publication No. 2006/0286170, U.S. Pat. No. 6,376,525, International Patent Application PCT/US2000/13420 (published as WO 2000/71129), International Patent Application PCT/US2010/038568 (published as WO 2010/147917), Russian Patent No. 2370264, International Patent Application PCT/EP2005/010311 (published as WO 2006/032518), International Patent Application PCT/US2003/032612 (published as WO 2005/034955), and Japanese Patent Application No. 19900061694 (published as JP 326147).